We studied the gene expression profiles of 9 prostate tumors from current smokers, 21 prostate tumors from past smokers, and 17 prostate tumors from never smokers. The smoking status was determined from medical records and cancer registry entries. We discovered a unique gene expression profile in prostate tumors associated with current smoking. A gene expression signature specific to B lymphocytes separated current smokers from past and never smokers. There was a residual effect of smoking in the gene signature of tumors from past smokers, however, the differences in gene expression were not statistically significant comparing tumors from past and never smokers. Thus, current smoking appears to induce a gene signature in prostate tumors that disappears with smoking cessation. This association of current smoking, but not past smoking, with a distinct gene expression profile in prostate tumors is consistent with the epidemiology of smoking in prostate cancer etiology. Here, only current smoking was found to be associated with a significantly increased risk of the metastatic disease, whereas smoking cessation and a past smoking status leads to the disappearance of the excess risk by current smoking. We corroborated these findings by immunohistochemistry and in situ hybridization studies using paraffin-embedded tumors from a second sample set. The two approaches corroborated that current smoking induces a B lymphocyte-related response in prostate tumors and provided preliminary evidence that current smoking may activate inflammation-related pathways in the tumor environment. Currently, we are assessing another sample set of macrodissected prostate tumors from our collaborators at Johns Hopkins University to further confirm the smoking-specific gene signature in these tumors. Our results link a smoking-induced B lymphocyte signature in prostate tumors to prostate cancer progression and metastasis.